EGFR mutant lung cancer is a subset of lung cancer with unique biological and clinical features. Over 70% of patients whose lung cancers harbor specific mutations within the exons encoding the tyrosine kinase domain of EGFR experience radiographic responses to the selective EGFR tyrosine kinase inhibitors (TKIs), gefitinib (Iressa) or eriotinib (Tarceva), and overall median survival is about 30 months. However, no patients are cured. After about one year, acquired resistance develops. In previous work, we showed that in addition to primary drug-sensitive EGFR mutations, tumor cells from more than half of patients with such acquired resistance contain a recurrent second-site mutation (T790M) in the EGFR kinase domain. We also demonstrated using mouse models of lung cancer that T790M-mediated resistance could be overcome by a novel combination ofthe second-generation EGFR TKI, afatinib (BIBW2992), and the anti-EGFR antibody, cetuximab. A Phase IB clinical trial ofthis combination in humans, based upon our data, has now shown unprecedented activity in this patient cohort, with a 95% clinical benefit rate and a 35% confirmed radiographic response rate. The clinical findings have stimulated new and critical biological questions to address. Here, based upon promising new preliminary data, we aim to 1) elucidate the role of HER2 in mediating sensitivity of T790M-harboring EGFR mutant lung cancer cells to afatinib/cetuximab, and 2) identify in EGFR mutant kinases intrinsic regulatory domains required for full kinase function. An improved understanding of mechanisms and modulators of sensitivity and resistance to EGFR inhibitors will hopefully allow us to treat/suppress the development of progressive disease and provide new insights into the biology of cancers driven by EGFR or other mutant receptor tyrosine kinases.